Rivaroxaban is named (S)-5-chloro-N-{[2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl]methyl}-2-thiophene-carboxamide and has the following structure:

Rivaroxaban is a direct factor Xa inhibitor (“xaban”). It acts directly upon Factor X in the coagulation cascade and hence may be used as an anticoagulant. It is marketed in a number of countries as Xarelto® as an oral anticoagulant. It has been indicated for the treatment of various thromboembolic diseases, see, for example, WO 01/47949 (the basic patent), WO 2004/060887 and WO 2007/039132.
Rivaroxaban may be prepared according to the procedures described in WO 01/47949 and WO 2004/060887. Rivaroxaban is obtained in WO 01/47949 as crystalline modification I by purifying the crude product using column chromatography with a dichloromethane/methanol eluent. It is further discussed in WO 2007/039132. Modification I has a melting point of approximately 230° C. and a characteristic DSC, X-ray powder diffractogram, IR spectrum, Raman spectrum, FIR spectrum and NIR spectrum as set out in FIGS. 1-6 of WO 2007/039132.
The characterising peaks are reported as follows.
XRPD 2θ (°): 8.9, 12.0, 14.3, 16.5, 17.4, 18.1, 19.5, 19.9, 21.7, 22.5, 23.4, 24.1, 24.5, 24.7, 25.6, 26.4, 26.7, 30.0, 30.1 and 31.8.
IR (cm−1): 564, 686, 708, 746, 757, 830, 846, 920, 991, 1011, 1056, 1077, 1120, 1146, 1163, 1219, 1286, 1307, 1323, 1341, 1374, 1411, 1429, 1470, 1486, 1517, 1546, 1605, 1646, 1669, 1737, 2867, 2895, 2936, 2976 and 3354.
Raman (cm−1): 84, 111, 642, 672, 687, 745, 779, 792, 1083, 1099, 1232, 1280, 1307, 1325, 1343, 1428, 1473, 1485, 1548, 1605, 1638, 1664, 1722, 2899, 2944, 2983 and 3074.
FIR (cm−1): 82, 97, 138, 169, 179, 210, 226, 247, 272, 283, 298, 303, 350, 394, 417, 438, 458, 475 and 484.
NIR (cm−1): 4082, 4142, 4170, 4228, 4299, 4376, 4429, 4479, 4633, 4791, 4877, 4907, 5081, 5760, 5885, 6002, 6441, 6564, 8473 and 8833.
A drawback of the procedures set out in WO 01/47949 and WO 2004/060887 is that column chromatography is required to prepare modification I. This is not a useful technique for scaling up the procedure. WO 2005/068456 discloses a purification of rivaroxaban by recrystallising from acetic acid. However, the polymorphic form is not reported. Moreover, acetic acid is difficult to remove from the final product and reacts with rivaroxaban on storage to produce undesirable impurities in the product.
WO 2007/039132 discloses other techniques for the purification of rivaroxaban, but these do not form the required modification I. The products are other solid state forms, including modification II, modification III, an amorphous form, a hydrate form, an NMP solvate and an inclusion compound with THF.
There remains a need in the art for a more efficient process for the preparation of modification I.